Epigenetics refers to the study of reversible, heritable changes in gene function without changes in nuclear DNA sequences. DNA methylation and post-transcriptional modification of histones are the two most common mechanisms of epigenetic regulation. Wherein histone acetylation modification is the most widely studied, which is regulated by the activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC). (Clinical epigenetics 2012, 4 (1), 5).
Abnormal expression or mutation of HDAC may lead to imbalance of histone acetylation, lead to changes in chromatin structure, inhibit cell growth, differentiation, and apoptosis-related gene expression, and help to improve tumor tolerance to chemotherapy, promote tumor cell proliferation, migration and angiogenesis, and at the same time inhibit the differentiation and apoptosis of tumor cells, thereby leading to tumorigenesis. (ANTIOXIDANTS & REDOX SIGNALING 2015, 23 (1), 99-126). HDAC inhibitors can achieve targeted treatment of tumors by remodeling epigenetic functions.
According to the latest Thompson Reuters Integrity data, more than 1,000 HDAC is are in different stages of drug development. Five of them have been approved to come into the market, which are: the first HDAC inhibitor vorinostat (SAHA, Zolinza) approved by the FDA in October in 2006, romidepsin (depsipeptide, FK228) from Gloucester, panobinostat (LBH589, Farydak) from Novartis, Belinostat from Spectrum, and Chidamide (Epidaza) from Shenzhen Micro Core company.
The inventors disclosed a class of bithiazole compounds (WO2012152208) which can be used as an HDAC inhibitor for the development of anti-tumor and multiple sclerosis drugs. Among them, the compound CFH367-C (bexanostat) showed good enzyme activity and tumor cell proliferation inhibitory activity (IC50<400 nM).

Also, 201410136196.7 disclosed a class of bithiazole HDAC inhibitors. These compounds not only have better inhibitory activity against HDAC (IC50=30 nM), but also have stronger inhibitory activity against multiple myeloma cell proliferation (IC50 can reach up to 100 nM level), and the therapeutic effect on clinical symptoms of EAE mice is obviously better than CFH367-C. However, subsequent studies have shown that the metabolic properties of this class of compounds are poor, in which the oral bioavailability of the representative compound GCJ403 is only 14.7%.

Therefore, it is very meaningful to develop an HDAC inhibitor with good metabolic properties.